Throughout this application, various references are referred to within parentheses. Disclosure of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
Receptors are molecules which selectively interact with other molecules. Receptor molecules perform a variety of tasks from selective binding of substrates to catalyzing chemical reactions. One example of a multifunctional receptor molecule is monoclonal antibodies. Monoclonal antibodies bind to other molecules (antigens) with very high selectivity, while in other cases they catalyze chemical reactions by selectively binding the transition states of those chemical reactions. Monoclonal antibodies are used as medicinal and diagnostic agents. Other receptor molecules are used as drug targeting molecules and are sometimes referred to as xe2x80x9cmagic bulletsxe2x80x9d. In all cases, the receptor molecules effectiveness is dependent upon its ability to bind molecular species (substrates) with high discrimination and selectivity, i.e. not bind other often closely related molecular species.
Antibodies are proteins produced in response to the presence of a foreign substrate (Stryer, L. Biochemistry, 3rd Edition, W. H. Freeman and Company, New York, 1988 and Schultz, P. G. Acc. Chem. Res., 1989, 22, 287). A foreign substrate capable of eliciting antibody formation is called an antigen. Each antibody has a highly specific affinity for the antigen which stimulated its synthesis. The free energy for an antibody binding its antigen is normally from 6-15 kcal/mol. Structure analysis of antibodies have indicated that most have an immunoglobulin structure. Immunoglobulins are flexible Y-Shape molecules and consists of two kinds of polypeptide chains named as light and heavy chains molecular weight (FIG. 1).
While other workers have used combinatorial methods to prepare peptide and oligomer libraries, applicants are the first to apply combinatorial techniques to generate receptor libraries and to methods to identify receptors for specific biological targets.
The invention is directed to synthetic receptor(s) which comprises a polyfunctional organic template covalently linked to two or more oligomers which may independently be the same or different and may independently be straight chain, cyclic or branched. The template may be linked to an identifier which uniquely defines the synthetic receptor. The identifier is a stable chemical molecule or a plurality of stable chemical molecules distinguishable and detectable to picomolar levels or may be an oligonucleotide. In an preferred embodiment, the template is covalently linked to a solid support which is linked to an identifier.
In addition, the invention includes methods of preparing synthetic receptors and synthetic receptor libraries. The synthetic library may be linked with identifiers such that the library comprises a plurality of different synthetic receptor members. The invention also provides methods for assaying a synthetic receptor library to determine suitable synthetic receptor(s) which (a) bind an acceptor molecule; (b) exhibit biological activity; (c) which catalyze a reaction or inhibit a catalyzed reaction; and (D) separate compounds in chromatography.